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The sleep switch: Hypothalamic control of sleep and wakefulness

Article  in  Trends in Neurosciences · January 2002


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726 Review TRENDS in Neurosciences Vol.24 No.12 December 2001

The sleep switch: hypothalamic


control of sleep and wakefulness
Clifford B. Saper, Thomas C. Chou and Thomas E. Scammell

More than 70 years ago, von Economo predicted a wake-promoting area in the available that discuss the homeostatic and circadian
posterior hypothalamus and a sleep-promoting region in the preoptic area. control of sleep7, the contributions of brainstem
Recent studies have dramatically confirmed these predictions. The cholinergic–monoaminergic interactions to rapid eye
ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons movement (REM)–non-REM (NREM) sleep
that are active during sleep and are necessary for normal sleep. The posterior oscillations8–10, and the role of the dopaminergic
lateral hypothalamus contains orexin/hypocretin neurons that are crucial for system in sleep regulation11. Our model of the
maintaining normal wakefulness. A model is proposed in which wake- and hypothalamic switching circuitry provides an effector
sleep-promoting neurons inhibit each other, which results in stable mechanism by which many of these other systems
wakefulness and sleep. Disruption of wake- or sleep-promoting pathways produce or prevent sleep.
results in behavioral state instability.
The cholinergic and monoaminergic substrates
During World War I, the world was swept by a of arousal
pandemic of encephalitis lethargica, a presumed viral In the years after World War II, Moruzzi, Magoun and
infection of the brain that caused a profound and many others contributed to identifying an ascending
prolonged state of sleepiness in most individuals. The pathway that regulates the level of forebrain
victims could be awakened briefly with sufficient wakefulness12. Transection of the brainstem at the
stimulation, but tended to sleep most of the time. A midpons or below did not reduce arousal, whereas
Viennese neurologist, Baron Constantin von Economo, slightly more rostral transections at a midcollicular
reported that this state of prolonged sleepiness was due level caused an acute loss of wakefulness. The wake-
to injury to the posterior hypothalamus and rostral promoting outflow from this crucial slab of tissue at
midbrain1. He also recognized that one group of the rostral pontine–caudal midbrain interface was
individuals infected during the same epidemic instead traced by anatomical and physiological techniques
had the opposite problem: a prolonged state of insomnia through the paramedian midbrain reticular formation
that occurred with lesions of the preoptic area and basal to the diencephalon, where it divided into two
forebrain. von Economo further hypothesized that branches. One pathway innervated the thalamus, and
lesions of the posterior diencephalon could cause the the second extended into the hypothalamus. Although
disease we now call narcolepsy, in which individuals this arousal system was termed the ascending
have a tendency to fall asleep at inappropriate times. reticular activating system, in fact its origins were
Based on his observations, von Economo predicted that identified only recently by the availability of modern
the region of the hypothalamus near the optic chiasm neuroanatomical tracer methods combined with
contains sleep-promoting neurons, whereas the immunohistochemistry (Fig. 1).
posterior hypothalamus contains neurons that promote The main origin of the thalamic projection from the
wakefulness. caudal midbrain and rostral pons was identified as the
In subsequent years, his observations on the sleep- cholinergic pedunculopontine and laterodorsal
producing effects of posterior lateral hypothalamic tegmental nuclei (PPT–LDT)13–15. This population of
injuries were reproduced by lesions in the brains of cholinergic neurons projects in a topographic fashion to
monkeys2, rats3 and cats4; and the insomnia- the thalamus, including the intralaminar nuclei16–18,
producing effects of lateral preoptic–basal forebrain but also to the thalamic relay nuclei and the reticular
injuries were demonstrated in rats3 and cats5. nucleus of the thalamus. The reticular nucleus is
Injections of the GABA-receptor agonist muscimol into thought to play a key role in regulating thalamic
these areas in cats produced results similar to that of activity, and the cholinergic influence is thought to be
Clifford B. Saper* the lesions, suggesting that wakefulness is promoted crucial in activating thalamocortical transmission19.
Thomas C. Chou by neurons in the posterior lateral hypothalamus and The activity of the PPT–LDT neurons varies with
Thomas E. Scammell sleep by neurons in the preoptic area6. However, the different behavioral states. During wakefulness,
Dept of Neurology and
Program in Neuroscience,
basic neuronal circuitry that causes wakefulness was when the cortical electroencephalogram (EEG) shows
Harvard Medical School, only clearly defined in the 1980s and early 1990s, and low-voltage fast activity, many PPT–LDT neurons fire
Beth Israel Deaconess the pathways responsible for the hypothalamic rapidly (Table 1). As the individual goes to sleep, the
Medical Center, Boston,
regulation of sleep began to emerge only in the past EEG waves become slower and larger; during this
MA 02215, USA.
*e-mail: csaper@ five years. This article focuses on these hypothalamic period, few PPT–LDT neurons are active. Periodically
caregroup.harvard.edu switching mechanisms. Other recent publications are during the night, the individual enters a very

http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(00)02002-6
Review TRENDS in Neurosciences Vol.24 No.12 December 2001 727

and the serotoninergic dorsal and median raphé


nuclei, as well as the parabrachial nucleus21. Their
axons run through the lateral hypothalamus, where
they are joined by histaminergic projections from the
tuberomammillary nucleus (TMN). Other neurons in
the lateral hypothalamic area, some of which contain
Thalamus the peptide neurotransmitters orexin (also known as
hypocretin)22 or melanin-concentrating hormone23,
join this projection, as do axons from the basal
LDT ACh
PPT
forebrain cholinergic nuclei (Fig. 1). Each of these
VLPO pathways projects diffusely to the cortex of the entire
GABA cerebral hemisphere.
TMN LC
Gal
HIST Raphé NA The neurons in the monoaminergic cell groups
have been closely studied for their relationship to
5-HT
behavioral state. Neurons in the locus coeruleus, the
TRENDS in Neurosciences dorsal raphé nucleus and the TMN all fire at
relatively characteristic rates, which are state
Fig. 1. The ascending arousal system sends projections from the dependent24–27. All three groups fire fastest during
brainstem and posterior hypothalamus throughout the forebrain. wakefulness, slow down with the EEG during NREM
Neurons of the laterodorsal tegmental nuclei and pedunculopontine
tegmental nuclei (LDT and PPT) (blue circles) send cholinergic fibers
sleep, and nearly stop firing during REM sleep.
(Ach) to many forebrain targets, including the thalamus, which then Hence, the differences in the firing of the cholinergic
regulate cortical activity. Aminergic nuclei (green circles) diffusely project and monoaminergic ascending arousal systems
throughout much of the forebrain, regulating the activity of cortical and characterize and probably regulate the production of
hypothalamic targets directly. Neurons of the tuberomammillary nucleus
(TMN) contain histamine (HIST), neurons of the raphé nuclei contain 5-HT
the different behavioral states (Table 1).
and neurons of the locus coeruleus (LC) contain noradrenaline (NA).
Sleep-promoting neurons of the ventrolateral preoptic nucleus (VLPO, The ‘off’ switch
red circle) contain GABA and galanin (Gal).
Because the firing of monoaminergic neurons is state
dependent, understanding the sources of inputs to
different state of active sleep, in which there are rapid these cell groups provides a window into the
eye movements (REM sleep), a loss of muscle tone, mechanisms that regulate wakefulness. Sherin and
except for the muscles involved in respiration, and a colleagues have found two major inputs to the TMN
low-voltage fast EEG, which resembles a waking core: (1) a population of diffusely distributed neurons
state. The PPT–LDT are released from tonic in the lateral hypothalamic area; and (2) a dense
monoamine-mediated inhibition and hence fire cluster of neurons in the ventrolateral preoptic
rapidly during REM sleep8–10,20. nucleus (VLPO cluster), surrounded medially and
If the thalamocortical system is activated in both dorsally by a more diffuse extension from the nucleus
wakefulness and REM sleep, what is the difference (extended VLPO)28,29. Injections of an anterograde
between these two states? One key distinction is the tracer have confirmed that the axons from the VLPO
activity in the hypothalamic branch of the ascending intensely innervate the cell bodies and proximal
arousal system (Fig. 1). Cell groups in the caudal dendrites of the TMN, as well as less intensely
midbrain and rostral pons that contribute to this innervating the dorsal and median raphé nuclei and
projection include the noradrenergic locus coeruleus the locus coeruleus29,30 (Fig. 2). The axons from the
VLPO also terminate within the cholinergic basal
Table 1. Sleep stages and physiological activitya forebrain and PPT–LDT groups, but do not appear to
Wakefulness NREM sleep REM sleep contact the cholinergic cell bodies.
Nearly 80% of the retrogradely labeled VLPO
EEG Fast, low voltage Slow, high voltage Fast, low voltage
neurons contain both the GABA-synthesizing enzyme
Eye movement Vision related Slow, infrequent Rapid glutamic acid decarboxylase and the peptide
Muscle tone ↑↑ ↑ 0 galanin29. Electron microscopy confirmed that the
LDT/PPT ↑ 0 ↑↑ VLPO terminals onto TMN neurons were
LC/DR/TMN ↑↑ ↑ 0 immunoreactive for GABA and make symmetric
VLPO cluster 0 ↑↑ ↑? synapses29. Because galanin and GABA are known to
VLPO extended 0 ↑? ↑↑ inhibit both TMN and neurons of the locus
coeruleus24,31–33, the descending projection from the
Orexin/hyprocretin ↑↑ 0? 0?
aFiring rates are as follows: two arrows = rapid firing, one arrow = slower firing, 0 = little or no
VLPO is likely to be inhibitory in nature29,34,35.
firing. Question marks represent hypothesized firing patterns for which there is as yet no firm To determine the relationship between VLPO
evidence. Abbreviations: DR, dorsal raphé nucleus; EEG, electroencephalogram; LC, locus activity and sleep–wake behavior, the expression of Fos
coeruleus; LDT, laterodorsal tegmental nuclei; NREM, nonrapid eye movement; PPT, protein immunoreactivity was examined, as a marker
pedunculopontine tegmental nuclei; REM, rapid eye movement; TMN, tuberomammillary nucleus;
VLPO, ventrolateral preoptic nucleus.
of neuronal activity in the VLPO across the wake–sleep
cycle28. The number of Fos-immunoreactive neurons in

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728 Review TRENDS in Neurosciences Vol.24 No.12 December 2001

Fig. 2. The projections microinjecting ibotenic acid41. Although previous


from the ventrolateral
studies have demonstrated insomnia after injury to
preoptic nucleus (VLPO)
to the main components this region, these lesions injured fiber pathways3,5 or
of the ascending arousal
Thalamus
involved much of the preoptic area beyond the VLPO
system. Axons from the (Refs 42,43). In order to analyze the lesions, the
VLPO directly innervate
the cell bodies and VLPO numbers of remaining Fos-immunoreactive cell bodies
proximal dendrites of in the VLPO cluster and the extended VLPO were
neurons in the major
TMN compared with the changes in sleep behavior.
monoamine arousal LDT/PPT
In animals with more than 70% bilateral cell loss
groups. Within the major
cholinergic groups, axons Raphé in the VLPO cluster, the amounts of both NREM and
from the VLPO mainly LC REM sleep were reduced by about 55% (Ref. 41). The
innervate interneurons, loss of neurons in the VLPO cluster correlated closely
rather than the principal
cholinergic cells.
with the loss of NREM (r=0.77), but did not correlate
Abbreviations: LC, locus significantly with loss of REM sleep. However, the
coeruleus; LDT, loss of Fos-immunoreactive neurons in the extended
laterodorsal tegmental
VLPO correlated closely with the loss of REM sleep
nuclei; PPT,
pedunculopontine (r=0.74), but did not show a significant correlation
TRENDS in Neurosciences
tegmental nuclei; TMN, with the loss of NREM sleep. Conversely, when rats
tuberomammillary were exposed to a period of darkness during the day, a
nucleus; VLPO,
the VLPO correlated closely with the amount of sleep condition that doubles REM sleep time, there was a
ventrolateral preoptic
nucleus. The blue circle the animals experienced during the hour before death. concomitant increase in Fos expression in the
indicates neurons of the Other animals were sleep deprived for 9 or 12 hours, to extended VLPO, but not the VLPO cluster (J. Lu
LDT and PPT; green circles dissociate Fos expression from the circadian cycle. et al., unpublished). Anatomical studies have shown
indicate aminergic nuclei;
and the red circle
These animals showed the same correlation of Fos that the projections to the locus coeruleus,
indicates the VLPO. expression in the VLPO and sleep. However, the dorsal–median raphé, and the PPT–LDT arise
animals that failed to fall asleep following deprivation predominantly from the extended VLPO, rather than
showed little or no Fos expression in the VLPO. Similar the VLPO cluster (J. Lu et al., unpublished)30,44.
results have since been obtained in mice, cats, degus These observations suggest that the VLPO contains
and Nile river rats (S. Gans et al., unpublished)36,37. specific subregions that are specialized for the control
Electrophysiological recordings have similarly of REM versus NREM sleep.
identified sleep-active neurons in the VLPO region38,39.
The rate of firing of VLPO neurons was nearly doubled The flip–flop and bistability
during sleep compared with waking, and it doubled The relationship between the VLPO and the major
again during the deep sleep that followed sleep monoamine groups appears to be reciprocal. The
deprivation. The firing rate of VLPO neurons was not VLPO is innervated by histaminergic axons from the
increased after sleep deprivation until the animals TMN, noradrenergic terminals from the locus
actually slept, so VLPO firing rates probably are not coeruleus and serotoninergic inputs from the
related to the degree of sleepiness, but instead the midbrain raphé nuclei45. Recordings from individual
production of sleep itself. VLPO neurons in hypothalamic slices show that
The chemical identity of the sleep-active VLPO they are inhibited by noradrenaline and by 5-HT
neurons has recently been determined by combining (Ref. 46). No responses to histamine were recorded,
in situ hybridization for galanin with but TMN neurons also contain GABA and galanin,
immunocytochemistry for Fos (S. Gaus et al. and which might inhibit the VLPO (Ref. 47).
J. Lu et al., unpublished). In sleeping rats, 80% of the The model shown in Fig. 3 is based on the
Fos-immunoreactive neurons in the VLPO cluster hypothesized mutual inhibition between the VLPO
(and 50% in the extended VLPO) also contained and the major arousal systems. Although the
galanin mRNA, and about half of the galanin mRNA- monoamine systems are emphasized, there might be
containing neurons in both parts of the nucleus had a other components of the arousal system that are not
Fos-immunoreactive nucleus. Galanin-positive illustrated here, such as neurons in the lateral
neurons of the VLPO were also sleep active in mice hypothalamic area, that would interact with the VLPO
and cats (S. Gaus et al., unpublished)40. A galanin- in a similar way. When VLPO neurons fire rapidly
containing cell group in the VLPO has also been during sleep, they would inhibit the monoaminergic
identified in monkeys and humans (S. Gaus et al., cell groups, thus disinhibiting and reinforcing their
unpublished), so this system appears to be a uniform own firing. Similarly, when monoamine neurons fire at
feature of mammalian brains. a high rate during wakefulness, they would inhibit the
VLPO, thereby disinhibiting their own firing. This
Is the VLPO necessary for sleep? reciprocal relationship is similar to a type of circuit
To determine whether the VLPO neurons are necessary that electrical engineers call a ‘flip–flop’48. The two
for producing sleep, Lu and colleagues produced small halves of a flip–flop circuit, by each strongly inhibiting
excitotoxic lesions in the lateral preoptic area by the other, create a feedback loop that is bistable, with

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Review TRENDS in Neurosciences Vol.24 No.12 December 2001 729

two possible stable patterns of firing and a tendency to


avoid intermediate states. Such properties would be ORX
GAL
very useful in sleep–wake regulation, as an animal
GABA? Stabilizes
that walked about while half asleep would be in
behavioral state
considerable danger. The net effect of this bistable
switch is that during the course of the day, animals ORX? ORX
spend nearly all of their time in either a clearly waking
or sleeping state, with relatively brief times spent in HIST FLIP–FLOP GAL
GABA prevents GABA
transitions.
The self-reinforcing firing patterns of the flip–flop intermediate states
VLPO TMN
switch produce a degree of resistance to switching Sleep Arousal
eVLPO LC/DR
when one side is firing briskly. This stability avoids
inappropriate changes in wake–sleep state when
NE GAL
input signals to the VLPO and the monoaminergic
5HT GABA
cell groups fluctuate transiently over the course of the
day. However, large scale influences, such as
circadian sleep drive or accumulated homeostatic GAL NE
need for sleep might gradually shift the relative GABA 5HT
balance of mutual inhibition. When this pressure to PPT
REM Waking
change becomes great enough, the same feedback Sleep
LDT
properties that allow the flip–flop circuit to resist TRENDS in Neurosciences
change will suddenly give way and rapidly produce a
reversal of firing patterns. The flip–flop switch Fig. 3. A model for reciprocal interactions between sleep- and wake-
therefore changes behavioral state infrequently but promoting brain regions, which produces a flip–flop switch. Inhibitory
pathways are shown in red, and the excitatory pathways in green. The
rapidly, in contrast to the homeostatic and circadian blue circle indicates neurons of the LDT and PPT; green boxes indicate
inputs, which change continuously and slowly. aminergic nuclei; and the red box indicates the VLPO. Aminergic
A crucial aspect of this bistable switch is that if the regions such as the TMN, LC and DR promote wakefulness by direct
excitatory effects on the cortex and by inhibition of sleep-promoting
firing of neurons on either side is substantially
neurons of the VLPO. During sleep, the VLPO inhibits amine-mediated
weakened, the switch is less stable. For example, arousal regions through GABAergic and galaninergic (GAL)
after lesions of the VLPO, the animals experience projections. Most innervation of the TMN originates in the VLPO core,
much more wakefulness, and the homeostatic drive and input to the LC and DR predominantly comes from the extended
VLPO. This inhibition of the amine-mediated arousal system disinhibits
for sleep might increase, forcing the balance in the
VLPO neurons, further stabilizing the production of sleep. The PPT and
circuit nearer to its transition point41. Thus, rats with LDT also contain REM-promoting cholinergic neurons. The extended
VLPO lesions fall asleep more frequently, but because VLPO (eVLPO) might promote REM sleep by disinhibiting the PPT–LDT;
the self-reinforcing properties of the circuit are its axons innervate interneurons within the PPT–LDT, as well as
aminergic neurons that normally inhibit REM-promoting cells in the
weaker, they switch back into wakefulness more PPT–LDT. Orexin/hypocretin neurons (ORX) in the lateral hypothalamic
frequently as well, with the result that both wake and area (LHA) might further stabilize behavioral state by increasing the
sleep bouts are shorter after VLPO lesions. activity of aminergic neurons, thus maintaining consistent inhibition of
sleep-promoting neurons in the VLPO and REM-promoting neurons in
the PPT–LDT. Unbroken lines represent neuronal pathways described in
Stabilizing the flip–flop the text. Broken black lines indicate influences of specific regions on
A similar deficit on the waking side of the mutually behavioral states. Abbreviations: DR, dorsal raphé nucleus; HIST,
inhibitory flip–flop circuit might produce abrupt and histamine; LC, locus coeruleus; LDT, laterodorsal tegmental nuclei; PPT,
pedunculopontine tegmental nuclei; REM, rapid eye movement; TMN,
unstable fluctuations in behavioral state in the tuberomammillary nucleus; VLPO, ventrolateral preoptic nucleus.
disorder known as narcolepsy. Individuals with
narcolepsy experience frequent and unwanted
transitions into sleep during wakefulness, and they orphan G-protein-coupled receptors, which they
tend to awaken more frequently from sleep as well. named ‘orexin A and B’, because the peptides
When placed in a quiet environment, they fall asleep appeared to promote feeding49. de Lecea et al.,
and transition into REM sleep far more rapidly than meanwhile, described two hypothalamic-specific
unaffected individuals. At times, they experience mRNAs coding for the same peptides, which they
fragments of REM sleep intermixed with termed ‘hypocretins’ because they were hypothalamic
wakefulness, such as loss of muscle tone while awake, peptides with sequence similarity to secretin50.
a condition known as cataplexy. However, when the full extent of the pathways
The origin of narcolepsy was not understood until containing the orexin/hypocretin peptides was
a dramatic series of events that unfolded during the revealed by immunocytochemistry51–53, it became
past three years. In 1998, two groups of investigators clear that the orexin/hypocretin neurons, like the
simultaneously discovered a family of peptide VLPO, innervated all of the components of the
neurotransmitters that was made by neurons in the ascending arousal system (Fig. 4). Orexin 1 receptors
lateral hypothalamus. Sakurai and co-workers were found in the locus coeruleus, orexin 2 receptors
identified two peptides in a screen for ligands for in the TMN and basal forebrain, and both types of

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730 Review TRENDS in Neurosciences Vol.24 No.12 December 2001

Fig. 4. Orexin neurons in sleep (R. Szymusiak, unpublished). However, neither


the lateral hypothalamic
orexin-deficient animals nor narcoleptic humans
area innervate all of the
components of the have excessive amounts of sleep, but instead they
ascending arousal have poor maintenance of both wakefulness and
system, as well as the CTX sleep, or dysfunctional switching.
cerebral cortex (CTX) Orexin
itself. Abbreviations:
What, then, can be the role of the orexin/hypocretin
BF, basal forebrain neurons in maintaining behavioral state? Recent
cholinergic nuclei; BF
TMN studies have shown that the orexin/hypocretin
LC, locus coeruleus; LDT/PPT
neurons might influence both sides of the flip–flop
LDT, laterodorsal
tegmental nuclei; Raphé circuit by direct projections to both the monoaminergic
PPT, pedunculopontine LC and cholinergic arousal cell groups, and to the VLPO
tegmental nuclei; region. Orexin/hypocretin increases the firing of
TMN, tuberomammillary
nucleus. Blue circles
neurons in the locus coeruleus62, the dorsal raphé
indicate cholinergic nucleus63 and the TMN (H. Hass, unpublished).
neurons of the BF, LDT and Although VLPO neurons do not appear to contain
PPT; green circles indicate
orexin/hypocretin receptors53, injection of
monoaminergic nuclei.
orexin/hypocretin into the preoptic area near the
TRENDS in Neurosciences
VLPO increases wakefulness and decreases both REM
and NREM sleep64, suggesting a presynaptic
receptors were found in the midbrain raphé nuclei mechanism of action (perhaps on monoaminergic
and mesopontine reticular formation54,55. Because axons). Orexin/hypocretin neurons therefore might act
both receptors are mainly excitatory, these as a ‘finger’, pressing the flip–flop switch into the
observations suggested that orexin/hypocretin might ‘wakeful’ position, and preventing inappropriate
help maintain wakefulness by increasing the activity switching into the ‘sleep’ position. In the absence of
of the ascending arousal system. such an influence, as seen in narcolepsy, the switch
In 1999, Chemelli et al. produced would be less stable, and more susceptible to sudden
orexin/hypocretin knockout mice53. These animals and inappropriate transitions.
suffered intermittent attacks during the active (dark) This model could also explain the rapid transitions
period, in which they would suddenly fall onto their into REM sleep, or fragments of REM sleep, that are
sides for a few minutes, then get up and resume their seen in narcoleptics. The TMN, raphé nuclei and locus
activities. Polysomnographic analysis showed that coeruleus contain orexin/hypocretin receptors54, and
these periods of behavioral arrest consisted of all three groups inhibit REM sleep10. In the absence of
episodes of atonia associated with an EEG that was an excitatory orexin input, the weakened arousal
consistent either with wakefulness (i.e. cataplexy) or influence and increased activity of the extended
REM sleep, findings that are suggestive of narcolepsy. VLPO would allow earlier and more frequent
Simultaneously, Nishino et al. found that canine transitions to the REM state. Interestingly, like the
narcolepsy was due to mutations in the gene for the animals with VLPO lesions, destabilizing the switch
type 2 orexin/hypocretin receptor56. The combination in narcolepsy also results in more frequent
of these two findings provide overwhelming evidence awakenings from sleep.
that the loss of orexin/hypocretin signaling via the
type 2 receptor is sufficient to produce the symptoms Concluding remarks
of narcolepsy. The absence of orexin in the Advances over the past five years have largely borne
hypothalamus and in the spinal fluid of humans with out the remarkable predictions of von Economo, which
narcolepsy has subsequently been confirmed57–59. were made over 70 years ago on the basis of clinical
The orexin/hypocretin neurons probably play an observations. The occurrence of insomnia in
important role in producing normal wakefulness. individuals with lesions of the preoptic area and basal
Kilduff and Peyron have hypothesized that these forebrain was almost certainly due to the involvement
neurons might be active during wakefulness and of the VLPO in these cases. The hypersomnolent
REM sleep60, but we predict that these cells are individuals clearly had lesions of the ascending arousal
predominantly wake active. Orexin neurons pathways at the midbrain–diencephalic junction. And
synthesize Fos protein during wakefulness, and the von Economo’s prediction that narcolepsy could be
number of Fos-positive orexin-containing neurons caused by lesions of the posterior diencephalon has
correlates closely with the amount of wakefulness, been proven true by the recognition that this region
whether it is naturally occurring, produced by sleep contains the orexin/hypocretin neurons, the loss of
deprivation or caused by stimulant drugs, such as which causes narcolepsy in humans. The recent
amphetamine or modafinil53,61. Extracellular progress in defining the components of the sleep
recordings from neurons in the perifornical region, switching system should allow us to understand better
which contains the orexin/hypocretin cell bodies, how slowly changing influences, such as homeostatic
confirm that cells in this area are predominantly and circadian drives, can produce rapid and discrete
wake active although some also fire during REM changes in behavioral state.

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